Temperature difference between jugular bulb and pulmonary artery is associated with neurological outcome in patients with severe traumatic brain injury: A post hoc analysis of a brain hypothermia study

Background The purpose of this study was to examine whether the temperature difference between the jugular bulb and pulmonary artery (ΔTjb-pa) is associated with the neurological outcome of patients with severe traumatic brain injury (TBI). Methods We conducted a post hoc analysis of a multicenter randomized controlled trial of mild therapeutic hypothermia (TH, 32.0–34.0°C) or fever control (FC, 35.5–37.0°C) for the patients with severe TBI. ΔTjb-pa averaged every 12 h and the variation in ΔTjb-pa were compared between patients with favorable (n = 39) and unfavorable (n = 37) neurological outcomes. These values were also compared in the TH and FC subgroups. Results The average ΔTjb-pa values in patients with favorable and unfavorable outcomes were 0.24 ± 0.23 and 0.06 ± 0.36°C, respectively (P < 0.001). ΔTjb-pa trended significantly higher in the favorable outcome patients than in the unfavorable outcome patients throughout the 120 h after onset of severe TBI (P < 0.001). The variation in ΔTjb-pa from 0 to 72 h was significantly lower in the favorable outcome patients than in the unfavorable outcome patients (0.8 ± 0.8 vs 1.8 ± 2.5°C, respectively, P = 0.013). From 72 to 120 h, there was no significant difference in the variation in ΔTjb-pa. Significant differences between patients with favorable and unfavorable outcomes in ΔTjb-pa and the variation in ΔTjb-pa were similar in the TH subgroup, but not evident in the FC subgroup. Conclusions A reduction in ΔTjb-pa and greater variation in ΔTjb-pa were associated with an unfavorable outcome in patients with severe TBI, especially those treated with TH. When treating severe TBI patients, it is important to understand that there will be differences in temperature reflecting the brain environment and the systemic temperature, depending on the severity and outcome of TBI during TH.


Introduction
The heterogeneity of brain insult and systemic instability make understanding the pathophysiology of severe traumatic brain injury (TBI) extremely difficult. Using our data from the Brain Hypothermia Study (B-HYPO Study) in Japan [1], we recently identified several factors associated with the neurological outcomes of patients with severe TBI during the early phase of targeted temperature management (TTM), including blood glucose [2], plasma potassium [3], the partial pressure of arterial oxygen [4], a difference between mixed and jugular venous oxygen saturations [5], and a mild reduction in heart rate after tachycardia [6].
Monitoring the core body temperature as measured in the brain, jugular bulb, pulmonary artery, tympanic membrane, bladder, or rectum, is essential in patients with severe TBI. Brain temperature depends on three main factors: regional brain heat production, cerebral blood flow, and the temperature of arterial blood in the brain [7]. It has been reported that brain temperature is higher than that measured at other sites in patients with TBI because the brain is a hyper-metabolic organ [7][8][9][10]. However, monitoring brain temperature is difficult in clinical situations because it is an invasive procedure. However, the temperature in the jugular bulb reflects the metabolic status of the brain because 99% of the jugular venous blood is drained from the intracerebral vasculature [11,12]. Mielck et al. reported that the blood temperature was significantly higher in the jugular bulb than in the aorta in patients undergoing elective coronary artery bypass graft surgery [13]. However, there are no reports of the core temperature measured in both the jugular bulb (T jb ) and pulmonary artery (T pa ) during TTM in patients with severe TBI.
We hypothesized that these core temperatures and the difference between them (ΔT jb-pa ) may reflect the cerebral pathophysiology of patients with severe TBI and may be associated with their neurological outcomes. Therefore, we calculated this difference (ΔT jb-pa ) and the variation in ΔT jb-pa using a post hoc analysis of the B-HYPO Study in Japan [1].

Patients
The association between ΔT jb-pa and the neurological outcomes of patients with severe TBI was examined using data from the B-HYPO Study, a prospective multicenter randomized controlled trial performed from December 2002 to September 2008 in Japan [1]. The protocol was approved by the Institutional Review Board of Yamaguchi University Hospital, as the corresponding institution. All participating hospital approved the protocol. The trial was registered on the University Hospital Medical Information Network database (UMIN-CTR, no. C000000231) in Japan and on the National Institutes of Health database (ClinicalTrials.Gov, Identifier NCT00134472) in the United States. The written informed consents were obtained from all inclusion cases. If patient was minor or unconsciousness, informed consents were obtained from a family member or guardians. Consent was waived unless a family member could consent within 2 h of the time of enrolment. In such cases, consent was obtained after the family's arrival.
Briefly, the inclusion criteria were an age of 15-69 years and a Glasgow Coma Scale (GCS) score of 4-8. Overall, 148 patients were randomly assigned in a 2:1 ratio to either the mild therapeutic hypothermia (TH, 32.0-34.0˚C, final n = 98) group or the fever control (FC, 35.5-37.0˚C, n = 50) group. Neurological outcome was assessed using the Glasgow Outcome Scale (GOS) score at 6 months. The present post hoc analysis was performed using data from 76 of the 148 patients for whom measurements of the two core body temperatures (jugular bulb and pulmonary artery) were available. The two core body temperatures were monitored using an internal jugular venous catheter (5.5 Fr Opticath, Dainabot, Tokyo, Japan) and a pulmonary artery catheter (8Fr S-G Thermodilution Catheter, Edwards Lifescience, Tokyo, Japan), respectively, which were equipped with a thermistor. The position of the tip of the jugular venous catheter was confirmed using anterior-posterior radiography. Forty-five and thirtyone patients were treated with TH and FC, respectively.

Treatments and monitoring of hemodynamic parameters
The treatments were performed as described in our previous article [1]. In brief, cooling was initiated within 2 h of the onset of TBI. Cooling blankets, a rapid cold fluid intravenous infusion (up to 1000 ml), and/or cold gastric lavage were used during the induction phase in both groups. Temperature control was based on T jb . The goal of temperature management in both groups was to achieve the target temperature within 6 h of the onset of TBI and to maintain this temperature for at least 72 h. The patients were rewarmed at a rate of <1˚C/day. After rewarming, the core body temperature was maintained at <38˚C until day 7 after the onset of TBI.

Data collection and study outcome
The hemodynamic data were recorded on day 0 (before the induction of TH or FC), day 1 and day 3 after the induction of TH or FC, and 1 day after rewarming (defined as the day on which the core body temperature reached 36˚C). Representative values for each day were recorded by the attending physician. Continuous data on T jb and T pa were recorded every 30 min throughout the measurement period. The primary outcome was the GOS score at 6 months after TBI. A favorable neurological outcome was defined as good recovery and moderate disability, and an unfavorable neurological outcome was defined as severe disability, persistent vegetative state, or death.

Statistical analyses
In the present post hoc analysis, we compared the baseline characteristics, hemodynamic parameters, T jb , T pa , and ΔT jb-pa between patients with favorable and unfavorable neurological outcomes. T jb , T pa , and ΔT jb-pa were averaged and presented every 12 h. Data missing from these temperature records (8.02%) were replaced with the mean value of the adjacent data. The variation in ΔT jb-pa , or the absolute range between the maximum and minimum recorded ΔT jb-pa from 0 to 72 h (induction and maintenance period of TTM) and from 72 to 120 h (after the rewarming period of TTM), was compared between patients with favorable and unfavorable neurological outcomes.
The variables are shown as means ± standard deviations (SD) or as numbers (percentages). Continuous variables at a single point were compared using Student's t test and categorical variables were compared using an χ 2 test. Continuous variables measured at multiple points were analyzed using two-way analysis of variance. When the difference was significant, the Bonferroni post hoc test was used to determine the specific group difference. Missing values were excluded from all analyses, except for temperature data. A P value of <0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics for Windows version 22 (IBM SPSS Inc., Chicago, IL, USA).

Patients' characteristics
In this post hoc study, data from 45 TH and 31 FC patients were analysed. Table 1 shows the patients' characteristics according to their neurological outcomes. The patients with favorable outcomes were significantly younger and had significantly higher GCS scores on admission than patients with unfavorable outcomes. The scores on the head CT scans did not differ significantly between the two groups. In the TH subgroup, there was no characteristic significant difference between patients with favorable and unfavorable outcomes. In the FC subgroup, the patients with unfavorable outcomes were significantly older and more were male than among the patients with favorable outcomes. There were infectious complications during TTM in five patients: one with meningitis, two with pneumonia, and two with bacteremia. There was no significant difference in infectious complications between patients with favorable and unfavorable outcomes, and the findings were similar for the FC and TH subgroups.

Hemodynamic parameters
In this study, the median intervals from the onset of TBI and data collection on days 0, 1, and 3 of treatment and 1 day after rewarming were 6.1 (2.0-9.2) h, 25 (19-29) h, 72 (67-76) h, and 162 (121-209) h, respectively. Tables 2-4 show the hemodynamic parameters of the patients in both the TH and FC subgroups, the TH subgroup, and the FC subgroup, respectively.
In all patients, MAP on day 0 and day 3 and CPP on day 0 were significantly higher in the patients with favorable outcome than in those with unfavorable outcomes (Table 2). However, there was no significance difference between the two groups in SjbO 2 , central venous pressure (CVP), CI, SvO 2 , or the systemic vascular resistance index (SVRI) on any day. In the TH subgroup, MAP on day 0 and day 3 and CPP on day 0 were significantly higher in the patients with favorable outcomes than in those with unfavorable outcomes (Table 3). In the FC subgroup, there were no significant differences in the hemodynamic parameters (Table 4). ICP tended to be lower among the total patients with favorable outcomes and in the TH subgroup patients with favorable outcomes than in those with unfavorable outcomes, but the difference was not statistically significant. CPP on day 0 was significantly higher among the total patients and the TH subgroup patients with favorable outcomes than in the corresponding patients with unfavorable outcomes. Fig 1 shows ΔT jb-pa plotted every 12 h from randomization to 120 h in all patients with favorable and unfavorable neurological outcomes. The average ΔT jb-pa values in the favorable and unfavorable outcome patients were 0.24 ± 0.23 and 0.06 ± 0.36˚C, respectively. ΔT jb-pa was significantly larger in the favorable outcome patients than in the unfavorable outcome patients at 7 of the 10 measurement points. The significant values of ΔT jb-pa were 0.28 ± 0.18˚C vs 0.00 ± 0.42˚C, respectively, P < 0.001 (24 h); 0.23 ± 0.18˚C vs 0.06 ± 0.24˚C, respectively, P = 0.001 (48 h); 0.24 ± 0.21˚C vs 0.01 ± 0.41˚C, respectively, P = 0.003 (60 h); 0.18 ± 0.34˚C vs

Discussion
In this post hoc study, we have demonstrated that ΔT jb-pa was significantly larger (around 0.25˚C) up to 120 h in the patients with neurologically favorable outcomes than in those (close to 0˚C) with unfavorable outcomes (Fig 1). Furthermore, the variation in ΔT jb-pa during the induction and maintenance periods of TTM was significantly lower in the patients with neurologically favorable outcomes (Table 5). These same differences were observed in the TH subgroup but not in the FC subgroup (Fig 2A and 2B, and Table 5). This is the first report to show that ΔT jb-pa reflects the neurological outcomes of patients with acute brain insult in a relatively early stage of TTM, especially during TH (Figs 1 and 2A). In this study, ΔT jb-pa was large (around 0.25˚C) in the neurologically favorable outcome patients, especially during treatment with TH (Figs 1 and 2A). In humans, the cerebral metabolic rates for glucose and oxygen are much higher than those of the whole body [15], so the temperature of the venous blood in the brain and jugular bulb may be much higher than that in the other systemic venous vasculature. The difference between the brain and pulmonary arterial temperatures was reported to be 0.3 ± 0.3˚C by Rossi et al. [7], and the mean ΔT jb-pa  was reported by Crowder et al. [11] to be 0.2˚C before craniotomy in neurosurgical patients. Mielck et al. also reported that the jugular bulb (blood) temperature was much higher than the systemic core body temperature [13]. These findings are consistent with our results in all patients with favorable outcomes and those patients in the TH subgroup with favorable neurological outcomes (Figs 1 and 2A), whose values for ICP and CPP were better than those of the patients with unfavorable neurological outcomes (Tables 2 and 3). In terms of their neurological outcomes at 6 months after the onset of severe TBI, ΔT jb-pa was positive (around 0.25˚C) in patients with favorable neurological outcomes but was near 0˚C in those with unfavorable neurological outcomes (Figs 1, 2A and 2B). Several factors might explain this difference. First, heat clearance from the brain may have been reduced in patients with unfavorable outcomes, in whom ICP was higher and CPP was lower, although many differences were not significant (Tables 2-4). Lower CPP may induce lower CBF and lower heat clearance from the brain. Second, heat production of the injured brain region itself may have been reduced in the patients with unfavorable outcomes. In our previous sub-analysis, the difference in oxygen saturation between the mixed venous blood and the jugular bulb blood tended to decrease on days 1 and 3 in patients with unfavorable outcomes [5]. This finding indicates that the cerebral metabolic rate for oxygen (CMRO 2 ) in these patients was suppressed. This phenomenon supports the present result that ΔT jb-pa was significantly smaller (close to 0˚C) in the neurologically unfavorable outcome patients (Figs 1 and 2A). Moreover, the thermal control center (hypothalamus) would have been damaged in the early stage of TTM by the severe TBI itself or by the regional ischemia caused by the reduction in CPP [16]. These phenomena may explain, at least in part, why ΔT jb-pa approached 0˚C in these patients with neurologically unfavorable outcomes (Figs 1, 2A and 2B). The results of this study did not demonstrate that ΔT jb-pa is an indicator for the treatment of severe TBI, but it may at least be useful in predicting patients' outcomes. In either case, when treating severe TBI, it should be noted that the temperature reflecting the brain environment and the systemic temperature will differ during TH depending on the severity or outcome of TBI.
In this study, the variation in ΔT jb-pa during the induction and maintenance periods of TTM was significantly larger in the patients with neurologically unfavorable outcomes, especially in the TH subgroup ( Table 5). The therapeutic temperature intervention itself has been reported to alter the difference (ΔT) between the brain and systemic temperatures in either direction, but prognosis has not been discussed in detail [17]. In this study, the variation in ΔT jb-pa was significantly larger in patients in the TH subgroup with unfavorable outcomes. The larger variation in ΔT jb-pa in patients with unfavorable outcomes may be related to the impairment of the temperature control center by the severe TBI itself and by patient care, such as a reduction in the regional cerebral blood flow. In either case, it is important to understand that any temperature control strategy that targets the systemic temperature in patients with severe TBI with unfavorable outcomes will not only alter the temperature reflecting the target organ of temperature control, the brain, but will also increase its variability.
This study had several limitations. First, the sample size was reduced at each point because data for T jb and T pa were not recorded for all patients. This may have biased the results of the study. Second, the physiological parameters used in the analysis were recorded only once on days 0, 1, and 3 of TTM maintenance and 1 day after rewarming, which limited the number of values recorded. Third, we did not collect blood data on infectious complications, so we could not consider the effect of infection on body temperature. However, there was no significant difference in the complication rate of infections between patients with favorable and unfavorable outcomes. Finally, we only conducted a post hoc analysis of data from the B-HYPO Study [1], and a prospective study is required to verify the usefulness of ΔT jb-pa in evaluating the outcomes of patients with severe TBI.